Pharmaceutical composition containing an acid-labile omeprazole and process for its preparation

ABSTRACT

A composition, particularly adapted for oral administration, containing omeprazole, and a method for preparing the composition, are disclosed. The composition, being exempt of alkaline-reacting compounds, contains a core constituted of nuclei and said benzimidazole, the nuclei and benzimidazole being compressed together, an intermediate layer, and an enteric layer.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 09/043,145,filed Aug. 3, 1998, pending.

BACKGROUND OF THE INVENTION

This present invention relates to a novel composition containing anacid-labile benzimidazole, and to its preparation. This novelcomposition is perfectly suitable for oral administration. The inventionalso relates to a process for preparing this composition.

Many substances, of pharmaceutical value, that are labile in an acidmedium have been described in the literature. The substances disclosedin the following patents can be given by way of example: EP 244 380,U.S. Pat. No. 4 045 563, EP-0 005 129, BE-898 880, GB-2 141 429, EP-0146 370, GB-2 082 580, EP-A-0 173 664, EP-A-0 080 602, EP-0127 763, EP-0134 400, EP-0 130 729, EP-0 150 586, DE-34 15971, GB-2 082 580,SE-A-8504048-3 and U.S. Pat. No. 4 182 766. On the other hand,omeprazole, which is of the family of benzimidazoles, corresponding toan anti-ulcer substance, used conventionally for decreasinggastrointestinal acid secretion, is well known and has been notablydiscussed in Swedish patent application 78.04231 filed on Apr. 14, 1978,as well as in numerous other patents. Pantoprazole and lansoprazolewhich both correspond to anti-ulcer substances of the omeprazole family,are notably discussed in U.S. Pat. No. 4,758,579 and in U.S. Pat. No.4,628,098 respectively.

Chemical substances that are easily destroyed in an acid medium (whichis expressed herein by the term “acid-labile” and meaning chemicalsubstances that are labile in an acid medium), such as benzimidazolesand, in particular, omeprazole, lansoprazole and pantoprazole, create aspecial problem for formulators when it is required to provide apharmaceutical form designed for oral administration. The product doesindeed come into contact with the stomach content, which is a highlyacid medium, leading to breakdown of these chemical substances.

In order to avoid contact between the substances and the acid gastricjuice following oral administration of the substance, a pharmaceuticalformulation is conventionally used, such as a capsule or table whichcontains a core (tablet, microgranule, pellet, etc . . . containing theacid-labile active substance and an outer layer that surrounds this coreand which consists of a gastro-resistant composition that isentero-soluble. Generally, the coating agent is a compound that isparticularly insoluble in an acid medium, but which is soluble in aneutral or alkaline medium.

For substances that are highly labile in an acid medium but which aremore stable in a neutral or alkaline medium, such as omeprazole,pantoprazole and lansoprazole, it is necessary to add an inert substanceto the composition, which leads to an alkaline reaction aimed atimproving stability of the active substance during manufacture thereof,and during storage of the pharmaceutical form.

Several prior art documents describe such compositions that are suitablefor oral administration of acid-labile substances.

EP-0,244,380 discloses pharmaceutical formulations that are suitable fororal administration of acid-labile substances. It is stated that theseacid-labile substances intended for oral administration must beprotected by an enteric coating, but conventional enteric coatings of anacid nature are not suitable for this purpose. If one were indeed tocover acid-labile substances which such coatings, the substance would berapidly decomposed due to direct or indirect contact with the coating,which manifests itself by a change of color and a decrease in the activesubstance content with the passage of time. The solution proposed inthat patent corresponds to formulations consisting of: (a) a core in theform of small particles, i.e. pellets or compressed powder, containingthe active substance along with an alkaline reacting compound, (b) oneor several inert intermediate layers containing excipients for tabletswhich are soluble, and which rapidly disintegrate in water,water-soluble film-forming polymer compounds optionally containingalkaline compounds acting as a pH buffer between the core having analkaline reaction and the outer layer, and (c) an outer layer consistingof an enteric composition. It is also stated that, in order to improvestorage stability, the cores containing the active substance should alsocontain constituents having an alkaline reaction, and that the waterthat enters by diffusion, or the gastric juice, will dissolve part ofthe core close to the enteric coating, forming an alkaline solution atthis level inside the coated form for administration. This patent claimspharmaceutical formulations containing acid-labile active substances offormula I with the notable exception of omeprazole.

EP-A-0,247,983 which is related to pharmaceutical formulations that aresuitable for oral administration of acid-labile substances adopts thegeneral principles developed in EP-A-0,244,380 in order to moreparticularly apply them to the case of omeprazole. The main claim inthat application thus covers the association of omeprazole with anauxiliary alkaline-reacting substance.

U.S. Pat. No. 4,786,505 discloses novel stable preparations containingomeprazole intended for oral administration, their preparation and amethod for treating gastrointestinal sicknesses using these novelpreparations. These oral pharmaceutical preparations comprise: (a) acore comprising omeprazole and an alkaline reacting compound, analkaline salt of omeprazole and an alkaline-reacting compound or analkaline salt of omeprazole alone; (b) at least one inert intermediatelayer that is water-soluble or rapidly disintegrates in water; and (c)an external layer comprising an enteric coating.

EP-A-0,519,365 discloses pharmaceutical formulations that are suitablefor oral administration of pantoprazole, comprising an acid-labilesubstance. In order to improve stability of pantoprazole formulations,this document discloses the use of the active substance in a salt form.The pharmaceutical formulations disclosed comprise: (a) a corecontaining the active principle in a salt form, (b) at least onewater-soluble intermediate layer and (c) an outer layer corresponding toan enteric coating. It is stated hat the use of a salt form in the coreenables an alkaline environment to be created that protects the activesubstance. If the salt form does not have a sufficient effect on the pH,it is necessary to add a constituent that has an alkaline reaction tothe core.

EP-A-0,519,144 discloses a novel process for producing a stablepreparation containing omeprazole, intended for oral administration.This document notably discloses a process for preparing pelletscontaining omeprazole in which a core constituted of inert substances iscovered by the active substance in finely divided form and dispersed inan aqueous dispersion buffered to a pH of 7.0, after which an entericcoating is applied, the finished product being placed inside a capsule.

U.S. Pat. No. 5,232,706 discloses novel stable pharmaceuticalpreparations containing omeprazole, intended for oral administration.The pharmaceutical compositions disclosed comprised: (a) a corecontaining omeprazole and an alkaline salt of omeprazole mixed with afirst alkaline-reacting compound; (b) at least one intermediate layerformed by an excipient and a second alkaline-reacting compound and (c)an outer layer formed by an enteric coating. It is stated that theproblem of the poor stability of the omeprazole is resolved, firstly, byincreasing the way the core behaves as a base either by introducingomeprazole in the form of an alkali metal or alkaline-earth salt, or amixture of omeprazole with a basic compound or by a combination of thesetwo possibilities; and secondly “by incorporating an intermediate layerbetween the core and the enteric coating for preventing the alkalinecore from causing breakdown of the enteric coating”.

FR-A-2,692,146 discloses stable compositions of microgranules ofgastro-protected omeprazole as well as their preparation. This documentsparticularly discloses a stable microgranule formulation of omeprazolecomprising a neutral core consisting of sugar and starch covered with anactive layer constituted by omeprazole diluted in mannitol insubstantially equal amounts, and an intermediate layer comprisingmannitol; an outer layer formed from an enteric coating being optionallypresent. There, it is indicated that the omeprazole is employed in adiluted powder form in an amount that is substantially equal to theamount of mannitol in order co protect the omeprazole from contact withsolvents and with traces of water present in the binder solutionsemployed for applying the mixture of omeprazole and mannitol to theneutral grains consisting of sugar and starch. Additionally, accordingto that patent, supplementary protection of the omeprazole applied coneutral grains is obtains by means of a second protective layerconsisting of mannitol and a binder solution in order to definitivelyisolate the core onto which the omeprazole and the mannitol is applied.This supplementary protection isolates the omeprazole from the outercoating layer that is designed to ensure gastro-protection of the activecores.

WO96/01624 in the name of ASTRA discloses a tableted dosage formcomprised of individually enteric coated layered units of a corematerial comprising a benzimidazole ingredient. Said individuallyenteric coated layered units are mixed with tablet excipients andcompressed together. Said tablet excipients are e.g. microcrystallinecellulose. The resulting tablet is aid to withstand acidic environment.

SUMMARY OF THE INVENTION

The applicant has studied possible novel pharmaceutical compositionsdesigned for oral administration of acid-labile substances, and notablyomeprazole, pantoprazole, lansoprazole, leminoprazole and pariprazole,which have excellent storage stability together with stability duringtheir preparation process, and has surprisingly found novel compositionsthat are particularly stable that do not include eitheralkaline-reacting compounds nor mannitol in a substantiallystoechiometric amount, which are both stated as being essential in theprior art.

Thus, the present invention provides a composition exempt ofalkaline-reacting compounds comprising:

(a)—a core containing an acid-labile benzimidazole active principle,said core being constituted of nuclei and said active ingredient mixedtogether and then compressed together, and said active principle notbeing in the form of an alkaline salt;

(b)—an intermediate layer; and

(c)—an enteric layer.

According to one embodiment, said nuclei and said active ingredient aregranulated together and then compressed together.

According to one preferred embodiment, the nuclei have a particle size,in the absence of the active principle, comprised between 80 and 500 μm,preferably comprised between 150 and 300 μm.

According to a preferred embodiment, in the composition, pharmaceuticalexcipients, preferable at least one lubricant, are additionally presentwith said nuclei and said active ingredient.

According to another embodiment, at least one lubricant selected fromthe group comprising: sodium stearylfumarate, magnesium stearate,glyceryl behenate and talc is additionally present with said nuclei andsaid active ingredient.

According to another embodiment, the intermediate layer containssilicium dioxide.

Omeprazole, lansoprazole, pantoprazole, leminoprazole or pariprazole areexamples of acid-labile benzimidazole active principle.

The invention also provides a method for preparing a compositionaccording to the invention, comprising the steps of:

(i) mixing nuclei with an active principle;

(ii) compressing the product of step (i) to form a core containing anactive principle;

(iii) coating said core with an intermediate layer; and

(iv) coating a product from step (iii) with an enteric layer.

According to an embodiment, step (i) is granulation.

According to another embodiment, said step (i) is carried out byspraying a medium containing an active principle onto nuclei in afluidized bed granulator followed by drying the product thus obtained.

The medium containing the active principle is preferably an aqueousmedium.

According to another embodiment, the instant process additionallycomprises the step of mixing nuclei or the product of step (i) withpharmaceutical excipients, preferably with at least one lubricant.

The invention will now be described in detail with reference to theattached drawings in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1(a)-(c) show the stability of the composition of example 1;

FIGS. 2(a)-(c) show the stability of a prior art composition, Prilosec®.

FIG. 3 is a photograph of granules obtained by fluidized bed granulationaccording to the examples.

DETAILED DESCRIPTION

Here, the expression “acid-labile substance” should be taken to meansubstances the breakdown half-life of which is less than 10 minutesand/or is comprised substantially between 10 minutes and 65 hours inaqueous solutions having, respectively a pH less than 4 and/or a pH of7. Typically, the active principles disclosed in EP 244,380 can be citedas examples, and notably omeprazole, pantoprazole, lansoprazole,leminoprazole and pariprazole.

Here, the expression “benzimidazole active principle” should be taken tomean benzimidazole derivatives that are of therapeutic value. Thebenzimidazole active principles disclosed in the description notablycomprise omeprazole, pantoprazole, lansoprazole, leminoprazole andpariprazole together with benzimidazole derivatives described in EP 244380, U.S. Pat. No. 4 045 563, EP-0 005 129, BE-898 880, GB-2 141 429,EP-0 146 370, GB-2 082 580, EP-A-0 173 664, EP-A-0 080 602, 30 EP- 0127763, EP-0 134 400, EP-0 130 729, EP-0 150 586, DE-34 15971, GB-2 082580, SE-A-8504048-3 and U.S. Pat. No. 4 182 766. In this invention, aredescribed preferably the compounds stated as being preferred in thosedocuments and in particular omeprazole, pantoprazole, lansoprazole,leminoprazole and pariprazole; the alkaline salt form of the activeprinciples cited above being excluded. Derivatives, such as salts(hydrates, etc.), esters and the like (including pro-drugs), are alsocontemplated, inasmuch as they are not of alkaline nature.

Mixtures of active principles are also envisaged, for example thosecomprising a benzimidazole in association with another active principle,or those containing two benzimidazoles.

Here, the expression “exempt of alkaline-reacting compound” should betaken to mean a composition that substantially does not contain anyalkaline-reacting compound, in other words a composition in which theamount of alkaline-reacting compound is not sufficient to set up analkaline micro-environment around the active principle when it is incontact with an acid or neutral aqueous medium, for example amicro-environment having a pH above 7.

According to this invention the core consists of a set of nuclei basedon pharmaceutical-inert excipients with which the acid-labile activeprinciple has been mixed, i.e. purely mixed, deposited, coated,aggregated, and then having been compressed together.

The expression “nuclei and active ingredient mixed together and thencompressed together” covers various embodiments.

According to one embodiment, the process used for the manufacture of theinstant cores is granulation, preferably fluidized bed granulation. Oneskilled in the art is fully aware of that technique. Elements ofinterest regarding said process may however be found in the publicationof Schaefer & Worts, Arch. Pharm. Chemi. Sci., Ed5, 1977, 51-60.According to said granulation technique, the nuclei, e.g. lactose, arefluidized together with the inlet air, and a (binder) solution of theactive ingredient is sprayed on the fluidized bed. Granules are thenformed of nuclei and active ingredient; said granules are morespecifically shown in FIG. 3. It can be seen that the solution formes abinder that holds together several nuclei; agglomeration also occursbetween nuclei and/or between benzimidazole particles. Said granules,which can be considered as intermediates, are then compressed together.

Alternative embodiments may be used, e.g. where the active ingredient ispresent onto the nuclei, which are then compressed together, or wherethe active ingredient and/or the nuclei are (partially) subject toagglomeration, and then agglomerated nuclei and/or agglomerated activeingredient and nuclei with active ingredient onto same are compressedtogether.

Another process that may be used for the manufacture is the tank coatingtechnique, where the nuclei are introduced into a solution of the activeingredient, and the resulting slurry is compressed, optionally after apreliminary drying step.

Another way to express the technique for manufacturing the nuclei+activeingredient is to call it “coating technique”, since a lot of possibleembodiments lead to products that can be qualified as “coated products”.Thus, in the instant description, the term “coating step” may be used inlieu of the term “mixing step”.

In fact, on a macroscopic scale, the core may be considered as a corehaving dispersed therein the active ingredient.

Here, the expression “a pharmaceutically-acceptable inert excipient”should be taken to mean a compound that does not lead to a chemicalreaction under operating conditions employed that can lead to breakdownof the active principle.

The nuclei can be any substance that is pharmaceutically inert vis-a-visthe active principle and can be crystalline or amorphous. These nucleimay, in general, be composed of a sugar, such as lactose, saccharose,corn starch etc. or any one of the mixtures thereof. The activeprinciple which is optionally mixed with pharmaceutical excipients, isapplied to the nuclei using any conventional coating technique employed,for example, in a suitable coating tank or in a fluidized bed devicesuch as a granulator, with the use of suitable aqueous and/or organicsolvents, or using a dry process. Coating is preferably carried out in afluidized bed granulator. Typically Polysorbate 80 or sodium laurylsulfate mixed with the active principle are added. Preferably, alubricant, and notably sodium stearylfumarate or magnesium stearate orglyceryl behenate (Ompritol 888 ATO) or (micronized) talc are addedafter the active principle has been deposited on the inert nuclei. Anyconventional excipients used in the pharmaceutical and chemical fieldthat are compatible with the active principle may be used, such asbinders, fillers, plastifiers, surfactants, pigments, disintegratingagents, lubricants, wetting agents, etc., excepting alkaline-reactingcompounds. The following can be cited as examples of excipients suitablefor use in the present invention: polysorbate 80 (Tween®80), sodiumlauryl sulfate, hydroxypropylcellulose, hydroxypropylmethylcellulose,talc, microcrystalline cellulose, colloidal silica,polyvinyl-pyrrolidone, sodium stearylfumarate, magnesium stearate,titanium dioxide, etc.

The intermediate layer, according to the invention consists of at leastone sub-layer. It corresponds to one or several inert water-solublelayers or layers which rapidly disintegrate in an aqueous medium,containing non-acid inert pharmaceutical excipients. This layercomprises at least one polymer conventionally used in applications wherea film is provided by coating such as: sugars, polyethyleneglycol,polyvinylpyrolidone, poly(vinyl alcohol), hydroxypropylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose, etc. Theintermediate layer can additionally contain any one of the conventionalpharmaceutical excipients cited in the section relating to the core, ora mixture thereof, and notably silicon dioxide. This silicon dioxide ispresent in an amount which can vary between 2 and 45% by weight based onthe dry weight of the intermediate layer, preferably 5 to 18% by weight,for example about 9%.

This intermediate layer is applied to the core using any coatingtechnique conventionally employed in a suitable coating tank or in afluidized bed device, with the use of suitable aqueous and/or organicsolvents, or by using latex suspensions of said excipients.

The enteric layer according to this invention corresponds to a layerthat is entero-soluble and gastro-resistant. It is applied to theintermediate layer by conventional coating techniques such as coating ina tank or a fluidized bed employing polymer solutions in water or insuitable organic solvents or using latex suspensions of these polymers.As a polymer, use can be made of: cellulose acetyl phthalate,hydroxypropyl-methylcellulose phthalate, polyvinyl phthalate acetate,methacrylic acid methyl esters/methacrylic acid copolymers, such as forexample, compounds known under the Eudragit®L12.5 or Eudragit®L100(R{overscore (o)}hm Pharma) trademarks, or similar compoundsconventionally employed for the preparation of enteric coatings, as wellas mixtures thereof.

The enteric coating can also be applied using aqueous dispersions ofpolymers, for example Aquateric® (FMC Corporation), Eudragit®L100-55(R{overscore (o)}hm Pharma), CE5142 coating (BASF). The enteric layercan also contain a pharmaceutically-acceptable plastifying agent suchas, for example, ketanol, triacetine, citric acid esters such as thoseknown under the Citroflex® (Pfizer) trademarks, phthalic acid esters,dibutylsuccinate or any other similar plastifying agent. The amount ofplastifying agent is in general optimized for each polymer and generallyrepresent 1 to 30% of the polymer, for example from 5 to 20%.Supplementary agents such as talc, pigments, coloring agents, flavoringagents, as well as any other excipient that conventionally enters intothe composition of enteric coatings can be employed.

The compositions according to the present invention generally comprise acore representing 40 to 90% by weight, preferably 60-70% by weight basedon the total weight of the composition, an intermediate layerrepresenting 5 to 30% by weight, preferably 15 to 20% by weight, basedon the total weight of the composition, and an enteric layerrepresenting from 5 to 30% by weight, preferably 15-20% by weight basedon the total weight of the composition. The core generally includes theactive principle and in an amount of from 2 to 50% preferably from 5 to20% by weight.

In one preferred embodiment, the composition according to the inventionis provided in a tablet form (single, beakable, etc.).

In another prefered embodiment, the composition is in the form ofmicro-tablets enclosed inside a capsule, e.g. a gelatin capsule. Forthis, any gelatin capsule conventionally employed in the pharmaceuticalformulation field can be used, such as the hard gelatin capsule known asCapsugel, available from Eli Lilly.

The compositions of this invention are particularly suitable for oraladministration of the active principles and are particularly suitablefor treating gastro-intestinal sicknesses.

According to one particular embodiment, the composition according tothis invention takes the form of a capsule containing 16 micro-tablets,having the following composition, expressed in mg/per capsule, startingfrom the core and moving outwards: lactose 50-500, active principle10-40, hydroxypropylmethylcellulose 1-100, Polysorbate 80 or sodiumlauryl sulfate 0.0-5.0, sodium stearylfumarate or magnesium stearate0.8-8.0, crospovidone 0-50; intermediate layer: talc 0-20, titaniumdioxide 0-20, silicon dioxide 0-20, hydroxypropylmethylcellulose 3-50;enteric layer: methacrylic acid copolymer, type C_(5-50,) triethylcitrate 0-15, talc 0-30.

The water needed to produce each component is present in an amount offrom 30 to 1000 as regards the core, 10-500 as regards of theintermediate layer and 0-1000 as regards the enteric layer. It ishowever also possible to use another medium, such as a medium containingwater and another solvent, such as alcohol.

The invention will now be described in more detail on the basis of thefollowing examples which are only provided by way of illustrativeexample.

EXAMPLE 1

Preparation of a Pharmaceutical Composition of Omeprazole Intended forOral Administration

A pharmaceutical composition according to the present invention, in theform of micro-tablets contained in a gelatin capsule having thefollowing composition, expressed in mg, was prepared.

1 - Composition of core: per per capsule microtablet (X16 tablets.)Omeprazole 1.250 20.00 Hydroxypropylmethylcellulose 0.625 10.00 Lactose11.875 190.00 Sodium stearylfumarate 0.150 2.40 Crospovidone 0.750 12.00Water 7.500 120.00

2 - Composition of intermediate layer per per capsule microtab1et (X16tablets.) Talc 0.375 6.00 Titanium dioxide 0.150 2.40Hydroxypropylmethylcellulose 0.750 12.00 Water 5.000 80.00

3 - Composition of the enteric layer per per capsule microtablet (X16tablets.) methacrylic acid copolymer, 1.375 22.00 type C triethylcitrate 0.206 3.30 Talc 0.275 4.40 Water 3.750 60.00

First, the core is prepared by dissolving hydroxypropylmethylcellulosein water followed by addition of the omeprazole and homogenization ofthe resulting suspension. The omeprazole suspension thus obtained issprayed onto lactose nuclei having a particle size of 250 μm, in asuitable fluidized bed granulator, such as a granulator sold by thecompanies Glatt, Aeromatic, etc. Any type of fluidized bed granulatorconventionally used for this type of step can be employed with thepresent invention. After all the suspension has been sprayed, the nucleiare dried in a conventional manner, using, for example a fluidized bed,the temperature of the product preferably remaining below 45° C. Thesodium stearylfumarate and the crospovidone are than added to the driednuclei, followed by mixing. After this, compression of the mixtureobtained is carried out to obtain microtablets of a diameter of about2.5 mm (generally comprised between 2 and 4 mm); alternatively,compression of the mixture obtained is carried out to obtain tablets ofconventional dimensions. The microtablets and the tablets containsuitable amounts of the active principle.

The intermediate layer which is prepared by dissolving thehydroxypropylmethylcellulose in water followed by addition of talc andtitanium dioxide followed up by homogenization, is deposited by sprayingonto the microtablets. This operation can be carried out in any suitablecoating device that allows a regular film to be obtained, for example aGlatt coater with a Würster type column.

The enteric layer, which is prepared by dissolving triethyl citrate in aportion of water, with addition to aqueous dispersion of methacrylicacid copolymer of type C (Eudragit L 30D-55), followed by agitation ofthe mixture obtained for 30 minutes and final addition of the talcsuspension that was prepared in parallel by homogenizing talc in theportion of water remaining, is deposited by spraying on the tabletcoated with the intermediate layer. In order to check the stability ofthe microtablets prepared according to the process described above, themicrotablets prepared were submitted to tests on their conservation at45° C. in the presence of 75% relative humidity. A prior art compositionsold under the name Prilosec®, was also tested. This prior artcomposition contains agents having an alkaline reaction. The amount ofomeprazole present in the microtablets at the end of the period ofstorage was determined by the following process: The amount ofomeprazole was determined bv HPLC on a Nucleosil C18 5μ 150×4.6 mmcolumn, using for the moving phase: buffer (8.9 g Na₂HPO₄, 2H₂O in 1000ml of purified water; pn adjusted to 7.6 using H₃PO₄) in an amount of73%/, acetonitrile in an amount of 27%. The detection consisted inmeasuring absorbency at 280nm.

The solution of the sample to be determines was prepared as follows. Anaccurately weighed amount of the microtablets, correspondingtheoretically to about 20 mg of omeprazole was introduced into a gauged50 ml flask. After adding the moving phase, this flask was placed in anultrasound bath for 5 minutes. After the solution had returned toambient temperature, the amount in the flask was adjusted to a volume of50 ml by adding the moving phase. The concentration, Cd, in omeprazole,expressed nn mg/theoretical weight of microtablets is given by thefollowing formula:

Cd=(Aech/Aet)×(Pet/Pech)×(Vd ech/Vd et)×Pth

in which: Aech=area of peak of sample solution; Aet=area of peak ofstandard solution, this solution having been prepared under the sameconditions as the sample solution but from a determined amount ofomeprazole (20 mg); Pet=weight of the standard substance; Pech=weight ofthe sample; Vd ech=dilution factor of the sample; Vd et=dilution factorof the standard; Pth=theoretical weight of the test sample ofmicrotablets (theoretically corresponding to 20 mg of omeprazole).

The results respectively obtained after 0 days, 14 days and 30 days aregiven in FIGS. 1 and 2 respectively for the composition according to theinvention and for Prilosec®. Curves 1 a and 2 a represent the initialstate, the respective percentages of the areas of the omeprazole peakbeing 99.67% and 97.51% for the composition according to the inventionand, respectively, Prilosec®. Curves 1 b and 2 b show the situationafter 14 days, the percentages then being 99.56% and 75.09%respectively. Curves 1 c and 2 c show the state after 30 days, thepercentages then being 99.38% and 15.89% respectively.

EXAMPLE 2

Preparation of a Pharmaceutical Composition of Omeprazole Intended forOral Administration

A pharmaceutical composition according to the present invention in theform of microtablets contained in a gelatin capsule having the followingcomposition expressed in mg, was prepared

1 - Composition of core: per per capsule microtablet (X16 tablets.)Omeprazole 1.250 20.00 Hydroxypropylmethylcellulose 0.625 10.00 Lactose11.875 190.00 Magnesium stearate 0.150 2.40 Crospovidone 0.750 12.00water 7.500 120.00

2 - Composition of intermediate layer per per capsule microtab1et (X16tablets.) Talc 0.375 6.00 Titanium dioxide 0.150 2.40Hydroxypropylmethylcellulose 0.750 12.00 Water 5.000 80.00

3 - Composition of the enteric layer per per capsule microtablet (X16tablets.) methacrylic acid copolymer, 1.375 22.00 type C triethylcitrate 0.206 3.30 Talc 0.275 4.40 Water 3.750 60.00

The pharmaceutical composition was prepared according to the methoddescribed in example 1, except that the sodium stearylfumarate wasreplaced by magnesium stearate.

The stability of the omeprazole microtablets obtained was evaluated bythe method described in example 1. The results obtained confirm thoseobtained for the composition according to example 1, the stabilityexpressed as a percentage of omeprazole in the peak at 30 days beingbetter than 99%.

EXAMPLE 3

Preparation of a Pharmaceutical Composition of Omeprazole Intended forOral Administration

A pharmaceutical composition according to the present invention in theform of microtablets contained in a gelatin capsule having the followingcomposition expressed in mg, was prepared

1 - Composition of core: per per capsule microtablet (X17 tablets.)Omeprazole 1.176 20.0 Hydroxypropylmethylcellulose 0.588 10.0 Lactose6.824 116.0 Sodium stearylfumarate 0.103 1.75 Crospovidone 1.603 27.25water 6.470 110.0

2 - Composition of intermediate layer per per capsule microtab1et (X17tablets.) Talc 0.294 5.00 Titanium dioxide 0.118 2.00Hydroxypropylmethylcellulose 0.588 10.0 water 4.000 68.0

3 - Composition of the enteric layer per per capsule microtablet (X17tablets.) methacrylic acid copolymer, 1.059 18.0 type C triethyl citrate0.159 2.70 Talc 0.212 3.60 Water 4.411 75.0

The pharmaceutical composition was prepared using the method describedin example 1.

The stability of the omeprazole microtablets obtained was evaluated bythe method described in example 1. The results obtained confirm thoseobtained for the composition according to example 1.

EXAMPLE 4

Preparation of a Pharmaceutical Composition of Omeprazole Intended forOral Administration

A pharmaceutical composition according to the present invention in theform of microtablets contained in a gelatin capsule having the followingcomposition expressed in mg, was prepared

1 - Composition of core: per per capsule microtablet (X17 tablets.)Omeprazole 1.176 20.0 Hydroxypropylmethylcellulose 0.588 10.0 Lactose6.824 116.0 sodium laurylsulfate 0.029 0.500 sodium stearylfumarate0.103 1.75 Crospovidone 0.603 27.25 Water 6.470 110.0

2 - Composition of the intermediate layer per per capsule microtablet(X17 tablets) Talc 0.294 5.00 Titanium dioxide 0.118 2.00Hydroxypropylmethylcellulose 0.588 10.0 Water 4.000 68.0

3 - Composition of the enteric layer per per capsule microtablet (X17tablets) Copolymer of methacrylic acid, 1.059 18.0 type C Triethylcitrate 0.159 2.70 Talc 0.212 3.60 Water 4.411 75.0

The pharmaceutical composition was prepared using the method of example1 except that, during the preparation of the core the sodiumlaurylsulfate was dissolved in water at the same time as thehydroxymethylpropylcellulose after which the omeprazole was put insuspension in this solution.

The stability of the omeprazole microtablets obtained was evaluated bythe method described in example 1. The results obtained confirm thoseobtained for the composition of example 1.

EXAMPLE 5

Preparation of a Pharmaceutical Composition of Omeprazole Intended forOral Administration

A pharmaceutical composition according to the present invention in theform of microtablets contained in a gelatin capsule having the followingcomposition expressed in mg, was prepared

1 - Composition of the core: per per capsule microtablet (X17 tablets)Omeprazole 1.176 20.0 Hydroxypropylmethylcellulose 0.588 10.0 Lactose6.824 116.0 Polysorbate 80 0.029 0.500 Sodium stearylfumarate 0.103 1.75Crospovidone 1.603 27.25 Water 6.470 110.0

2 - Composition of the intermediate layer per per capsule microtablet(X17 tablets) Talc 0.294 5.00 Titanium dioxide 0.118 2.00Hydroxypropylmethylcellulose 0.588 10.0 Water 4.000 68.0

3 - Composition of the enteric layer per per capsule microtablet (X17tablets) Methacrylic.acid, copolymer 1.059 18.0 type C Triethyl citrate0.159 2.70 Talc 0.212 3.60 Water 4.411 75.0

The pharmaceutical composition was prepared using the method describedin example 1, except for the fact that during preparation of the core,Polysorbate 80 was dissolved in water at the same time as thehydroxymethylpropylcellulose after which the omeprazole was put insuspension in this solution.

The stability of the omeprazole microtablets (measured as in example 1)confirmed the results obtained for the composition according to example1.

EXAMPLES 6 to 8

Preparation of Pharmaceutical Compositions of Pantoprazole for OralAdministration

The pharmaceutical compositions according to the invention in the formof individual tablets containing 40 mg of pantoprazole active principlehaving the following composition expressed in mg/tablet were prepared.

1 - Composition of the core: Ex. Ex. Ex. No.6 No.7 No.8 Pantoprazole40.00 40.00 40.00 Hydroxypropylmethylcellulose 20.00 20.00 20.00 Lactose120.00 120.00 120.00 Polysorbate 80 — 1.00 — Sodium laurylsulfate — —1.00 Sodium stearylfumarate 1.00 1.00 1.00 Crospovidone 20.00 20.0020.00 Water 250.0 250.0 250.0

2 - Composition of the intermediate layer Ex. Ex. Ex. No.6 No.7 No.8Talc 2.5 2.5 2.5 Titanium dioxide 1.0 1.0 1.0Hydroxypropylmethylcellulose 5.0 5.0 5.0 Water 35.0 35.0 35.0

3 - Composition of the enteric layer Ex. Ex. Ex. No.6 No.7 No.8Methacrylic acid copolymer, 10.00 10.00 10.00 type C triethyl citrate1.5 1.5 1.5 Talc 2.0 2.0 2.0 Water 40.0 40.0 40.0

The pharmaceutical composition was prepared using the method describedin example 1, except that firstly, during preparation of the core of thecompositions of examples 7 and 8, Polysorbate 80 and, respectively,sodium lauryl sulfate were dissolved in the water at the same time asthe hydroxymethylpropylcellulose after which the pantoprazole was putinto the suspension in the solution and, secondly, the final compositionwas obtained in the form of tablets, and not microtablets contained in acapsule.

The stability of the pantoprazole tablets obtained was evaluated by themethod described in example 1. The results obtained confirm thoseobtained for the composition according to example 1.

EXAMPLES 9-11

Preparation of Pharmaceutical Composition of Lansoprazole for OralAdministration

Pharmaceutical compositions according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/capsule were prepared.

1 - Composition of the core: Ex. Ex. Ex. No.9 No.10 No.11 lanzoprazole30.00 30.00 30.00 Hydroxypropylmethylcellulose 15.00 15.00 15.00 Lactose120.00 120.00 120.00 Polysorbate 80 — 0.75 — Sodium laurylsulfate — —0.75 Sodium stearylfumarate 1.25 1.25 1.25 Crospovidone 20.00 20.0020.00 Water 200.0 200.0 200.0

2 - Composition of the intermediate layer Ex. Ex. Ex. No.6 No.7 No.8Talc 5.0 5.0 5.0 Titanium dioxide 2.0 2.0 2.0Hydroxypropylmethylcellulose 10.0 10.0 10.0 Water 68.0 68.0 68.0

3 - Composition of the enteric layer Ex. Ex. Ex. No.9 No.10 No.11Methacrylic acid copolymer, 18.0 10.0 10.0 type C Triethyl citrate 2.72.7 2.7 Talc 3.6 3.6 3.6 Water 75.0 75.0 75.0

The pharmaceutical composition was prepared using the method describedin example 1, except that firstly, during preparation of the core of thecompositions of examples 10 and 11, Polysorbate 80 and, respectively,sodium lauryl sulfate were dissolved in the water at the same time asthe hydroxymethylpropylcellulose after which the pantoprazole was putinto the suspension in the solution.

The stability of the pantoprazole tablets obtained was evaluated by themethod described in example 1. The results obtained confirm thoseobtained for the composition according to example 1.

EXAMPLE 12

Preparation of Pharmaceutical Composition of Omeprazole for OralAdministration

A pharmaceutical composition according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/was prepared

1 - Composition of the core: per per capsule microtablet (X17 tablets)Omeprazole 1.176 20.0 Hydroxypropylmethylcellulose 0.588 10.0 Lactose6.823 116.0 Polyplasdone XL 1.603 27.25 Sodium stearylfumarate 0.1031.75 Water 6.471 110.0

2 - Composition of the intermediate layer per per capsule microtablet(X17 tablets) Talc (micronized) 0.176 3.00 Titanium dioxide 0.118 2.00Hydroxypropylmethylcellulose 0.588 10.0 Silicon dioxide 0.088 1.50 Water5.588 95.00

3 - Composition of the enteric layer per per capsule microtablet (X17tablets) Eudragit L 30D 55 (solid) 1.059 18.0 Triethyl citrate 0.1592.70 Talc (micronized) 0.212 3.60 Water 4.412 75.0

The pharmaceutical composition was prepared using the method describedin the examples above.

The stability of the microtablets of omeprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLE 13

Preparation of a Pharmaceutical Composition of Omeprazole for OralAdministration

A pharmaceutical composition according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/was prepared

1 - Composition of the core: per per capsule microtablet (X17 tablets)Omeprazole 1.176 20.0 Hydroxypropylmethylcellulose 0.588 10.0 Lactose6.823 116.0 Polyplasdone XL 1.603 27.25 Glyceryl behenate 0.103 1.75Water 6.471 110.0

2 - Composition of the intermediate layer per per capsule microtablet(X17 tablets) Talc (micronized) 0.176 3.00 Titanium dioxide 0.118 2.00Hydroxypropylmethylcellulose 0.588 10.0 Silicon dioxide 0.088 1.50 Water5.588 95.00

3 - Composition of the enteric layer per per capsule microtablet (X17tablets) Eudragit L 30D 55 (solid) 1.059 18.0 Triethyl citrate 0.1592.70 Talc (micronized) 0.212 3.60 Water 4.412 75.0

The pharmaceutical composition was prepared using the process describedfor the examples above.

The stability of the microtablets of omeprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLE 14

Preparation of Pharmaceutical Composition of Omeprazole for OralAdministration

A pharmaceutical composition according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/was prepared

1 - Composition of the core: per per capsule microtablet (X17 tablets)Omeprazole 1.176 20.0 Hydroxypropylmethylcellulose 0.588 10.0 Lactose6.823 116.0 Polyplasdone XL 1.603 27.25 Talc (micronized) 0.103 1.75Water 6.471 110.0

2 - Composition of the intermediate layer per per capsule microtablet(X17 tablets) Talc (micronized) 0.176 3.00 Titanium dioxide 0.118 2.00Hydroxypropylmethylcellulose 0.588 10.0 Silicon dioxide 0.088 1.50 Water5.588 95.00

3 - Composition of the enteric layer per per capsule microtablet (X17tablets) Eudragit L 30D 55 (solid) 1.059 18.0 Triethyl citrate 0.1592.70 Talc (micronized) 0.212 3.60 Water 4.412 75.0

The pharmaceutical composition was prepared using the process describedfor the examples above.

The stability of the microtablets of omeprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLES 15-17

Preparation of Pharmaceutical Composition of Lansoprazole for OralAdministration

Pharmaceutical composition according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/capsule were prepared.

1- Composition of the core: Ex. Ex. Ex. No. 15 No. 16 No. 17lanzoprazole 30.00 30.00 30.00 Hydroxypropylmethylcellulose 15.00 15.0015.00 Lactose 120.00 120.00 120.00 Polysorbate 80 — 0.75 — Sodiumlaurylsulfate — — 0.75 Glyceryl behenate 1.25 1.25 1.25 Crospovidone20.00 20.00 20.00 Water 200.0 200.0 200.0

2- Composition of the intermediate layer Ex. Ex. Ex. No. 15 No. 16 No.17 Talc 5.0 5.0 5.0 Titanium dioxide 2.0 2.0 2.0Hydroxypropylmethylcellulose 10.0 10.0 10.0 Water 68.0 68.0 68.0

3- Composition of the enteric layer Ex. Ex. Ex. No. 15 No. 16 No. 17Methacrylic acid copolymer, 18.0 10.0 10.0 type C Triethyl citrate 2.72.7 2.7 Talc 3.6 3.6 3.6 Water 75.0 75.0 75.0

The pharmaceutical composition was prepared by the method described inexamples 9 to 11, except that, during preparation of the core, glycerylbehenate was employed instead of sodium stearyl fumarate.

The stability of the microtablets of lansoprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

Examples 18-20

Preparation of Pharmaceutical Composition of Lansoprazole for OralAdministration

Pharmaceutical compositions according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/capsule were prepared.

1- Composition of the core: Ex. Ex. Ex. No. 18 No. 19 No. 20lanzoprazole 30.00 30.00 30.00 Hydroxypropylmethylcellulose 15.00 15.0015.00 Lactose 120.00 120.00 120.00 Polysorbate 80 — 0.75 — Sodiumlaurylsulfate — — 0.75 Talc (micronized) 1.25 1.25 1.25 Crospovidone20.00 20.00 20.00 Water 200.0 200.0 200.0

2- Composition of the intermediate layer Ex. Ex. Ex. No. 18 No. 19 No.20 Talc 5.0 5.0 5.0 Titanium dioxide 2.0 2.0 2.0Hydroxypropylmethylcellulose 10.0 10.0 10.0 Water 68.0 68.0 68.0

3- Composition of the enteric layer Ex. Ex. Ex. No. 18 No. 19 No. 20Methacrylic acid copolymer, 18.0 10.0 10.0 type C Triethyl citrate 2.72.7 2.7 Talc 3.6 3.6 3.6 Water 75.0 75.0 75.0

The pharmaceutical composition was prepared by the method described inexamples 9 to 11, except that, during preparation of the core,micronized talc was employed instead of sodium stearyl fumarate.

The stability of the microtablets of lansoprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLES 21-23

Preparation of Pharmaceutical Compositions of Pantoprazole for OralAdministration

The pharmaceutical compositions according to the invention in the formof individual tablets containing 40 mg of pantoprazole active principlehaving the following composition expressed in mg/tablet were prepared.

1- Composition of the core: Ex. Ex. Ex. No. 21 No. 22 No. 23Pantoprazole 40.00 40.00 40.00 Hydroxypropylmethylcellulose 20.00 20.0020.00 Lactose 120.00 120.00 120.00 Polysorbate 80 — 1.00 — sodiumlaurylsulfate — — 1.00 Glyceryl behenate 1.00 1.00 1.00 Crospovidone20.00 20.00 20.00 Water 250.0 250.0 250.0

2- Composition of the intermediate layer Ex. Ex. Ex. No. 21 No. 22 No.23 Talc 2.5 2.5 2.5 Titanium dioxide 1.0 1.0 1.0Hydroxypropylmethylcellulose 5.0 5.0 5.0 Water 35.0 35.0 35.0

3- Composition of the enteric layer Ex. Ex. Ex. No. 21 No. 22 No. 23Methacrylic acid copolymer, 10.00 10.00 10.00 type C Triethyl citrate1.5 1.5 1.5 Talc 2.0 2.0 2.0 Water 40.0 40.0 40.0

The pharmaceutical composition was prepared by the method described inexamples 6 to 8, except that, during preparation of the core, glycerylbehenate was employed instead of sodium stearyl fumarate.

The stability of the microtablets of pantoprazole (measured like inexample 1) confirms the results obtained for the composition accordingto example 1.

EXAMPLES 24-26

Preparation of Pharmaceutical Compositions of Pantoprazole for OralAdministration

The pharmaceutical compositions according to the invention in the formof individual tablets containing 40 mg of pantoprazole active principlehaving the following composition expressed in mg/tablet were prepared.

1- Composition of the core: Ex. Ex. Ex. No. 24 No. 25 No. 26Pantoprazole 40.00 40.00 40.00 Hydroxypropylmethylcellulose 20.00 20.0020.00 Lactose 120.00 120.00 120.00 Polysorbate 80 — 1.00 — Sodiumlaurylsulfate — — 1.00 Talc (micronized) 1.00 1.00 1.00 Crospovidone20.00 20.00 20.00 Water 250.0 250.0 250.0

2- Composition of the intermediate layer Ex. Ex. Ex. No. 24 No. 25 No.26 Talc 2.5 2.5 2.5 Titanium dioxide 1.0 1.0 1.0Hydroxypropylmethylcellulose 5.0 5.0 5.0 Water 35.0 35.0 35.0

3- Composition of the enteric layer Ex. Ex. Ex. No. 24 No. 25 No. 26Methacrylic acid copolymer, 10.00 10.00 10.00 type C Triethyl citrate1.5 1.5 1.5 Talc 2.0 2.0 2.0 Water 40.0 40.0 40.0

The pharmaceutical composition was prepared by the method described inexamples 6 to 8, except that, during preparation of the core, micronizedtalc was employed instead of sodium stearyl fumarate.

The stability of the microtablets of pantoprazole (measured like inexample 1) confirms the results obtained for the composition accordingto example 1.

COMPARATIVE EXAMPLE

The instant micro-tablet of example 1 are recompressed in amicrocrystalline cellulose matrix using the general procedure describedin the examples of WO96/01624. The resulting tablets show cracks ontheir surfaces, evidencing that recompression of the microtablets of theinvention according to the procedure described in the WO96/01624 patentis not successful in producing suitable tablets.

Further, said final tablets have been tested as to their dissolution ina 0.1N HCl solution, according to the general procedure described inWO96/01624. Results show that after 2 hours, the dissolution is about55%, evidencing that said final tablets cannot withstand acidicconditions.

It is clear that the particular pharmaceutical excipients described inthe compositions of examples 1 to 26 can be replaced by otherpharmaceutical excipients having the same function and which areconventionally employed in the pharmaceutical formulation field,provided that they are chemically compatible with the active principle.

All such alternative embodiments are covered by the scope of theinvention to the extent where the stability of the resultingpharmaceutical composition is not substantially affected.

The teaching of the invention extends in fact to any of the acid-labileactive principles mentioned in the introductory part of thisspecification, and notably those of the preferred embodiments and fromthe examples from the prior art. The mixing (e.g. coating, pure mixingor granulating) step of the process according to the invention can becarried out using any known technique conventionally used for thispurpose. Examples which can be mentioned are coating by immersion, drycoating, dry mixing, spray coating, spray mixing, etc.

Finally, it should be noted that additional layers or sub-layers can beadded, for the purposes of adding flavor and/or color, and/or improvingacceptability of the medicament and/or allowing it to be marked.

What is claimed is:
 1. A process for preparing a composition exempt ofalkaline-reacting compounds comprising: (a) a core containing anacid-labile omeprazole active principle, said core comprisingpharmaceutically inert nuclei and said active ingredient granulatedtogether and then compressed together, and said omeprazole activeprinciple being in a form different form an alkaline salt; (b) anintermediate layer; and (c) an enteric layer, comprising the steps of(i) granulating nuclei with the active principle; (ii) compressing theproduct of step (i) to form a core containing the active principle;(iii) coating said core with the intermediate layer; and (iv) coating aproduct from step (iii) with the enteric layer.
 2. The process accordingto claim 1, in which step (i) is performed by spraying a mediumcontaining the active principle onto nuclei in a fluidized bedgranulator followed by drying the product thus obtained.
 3. The processaccording to claim 2, in which the medium containing the activeprinciple is an aqueous medium.
 4. The process according to claim 1, inwhich said nuclei have a particle size, in the absence of the activeprinciple, comprised between 80 and 500 μm.
 5. The process according toclaim 1, in which said nuclei have a particle size, in the absence ofthe active principle, comprised between 150 and 300 μm.
 6. The processaccording to claim 5, additionally comprising the step of mixing theproduct of step (i) with at least one lubricant.
 7. The processaccording to claim 6, wherein said lubricant is selected from the groupconsisting of sodium stearylfumrate, magnesium stearate, glycerylbehenate, and talc.
 8. The process according to claim 1, in which theintermediate layer comprises silicon dioxide.
 9. The process accordingto claim 3, in which said nuclei have a particle size, in the absence ofthe active principle, comprised between 80 and 500 μm.
 10. The processaccording to claim 9, in which said nuclei have a particle size, in theabsence of the active principle, comprised between 150 and 300 μm.
 11. Astable drug composition exempt of alkaline-reactinq compoundscomprising: (a) a core containing all acid-labile omeprazole activeprinciple, said core comprising pharmaceutical inert nuclei and saidactive ingredient granulated together and then compressed together andsaid omeprazole active principle being in a form different from analkaline salt; (b) an intermediate layer; and (c) an enteric layer,wherein the composition is obtained by a process comprising the stepsof: (i) granulating nuclei with an active principle; (ii) compressingthe product of step (i) to form a core containing the active principle;(iii) coating said core with an intermediate layer; and (iv) coating aproduct from step (iii) with an enteric layer.
 12. The compositionaccording to claim 7, in which step (i) is carried out by spraying amedium containing an active principle onto nuclei in a fluidized bedgranulator followed by drying the product thus obtained.
 13. Thecomposition according to claim 12, in which the medium containing theactive principle is an aqueous medium.
 14. The composition according toclaim, 12, in which said nuclei have a particle size, in the absence ofthe active principle, comprised between 80 and 500 μm.
 15. Thecomposition according to claim 14, in which said nuclei have a particlesize, in the absence of the active principle, comprised between 150 and300 μm.
 16. The process according to claim 13, in which said nuclei havea particle size, in the absence of the active principle, comprisedbetween 80 arid 500 μm.
 17. The process according to claim 16, in whichsaid nuclei have a particle size, in the absence of the activeprinciple, comprised between 150 and 300 μm.
 18. The compositionaccording to claim 11, in which at least one lubricant is additionallypresent with said nuclei and said active ingredient.
 19. The compositionaccording to claim 10 wherein said lubricant is selected from the groupconsisting of sodium stearylfumarate, magnesium stearate, glycerylbehenate, and talc.
 20. The composition according to claim 11, in whichthe intermediate layer contains silicon dioxide.
 21. The compositionaccording to claim 16, in which at least one lubricant, is additionallypresent with said nuclei and said active ingredient.
 22. The compositionaccording to claim 21, wherein said lubricant is selected from the groupconsisting of sodium stearylfumarate, magnesium stearate, glycerylbehenate, and talc.
 23. The composition according to claim 16, in whichthe intermediate layer contains silicon dioxide.
 24. The compositionaccording to claim 11, provided in a tablet form.
 25. The compositionaccording to claim 13, provided in a table form.
 26. The compositionaccording to claim 15, provided in a tablet form.
 27. The compositionaccording to claim 17, provided in a tablet form.
 28. The compositionaccording to claim 11, provided in the form of microtablets enclosedinside a capsule.
 29. The composition according to claim 13, provided inthe form of microtablets enclosed inside a capsule.
 30. The compositionaccording to claim 15, provided in the form of microtablets enclosedinside a capsule.
 31. The composition according to claim 17, provided inthe form of microtablets enclosed inside a capsule.